Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved October 16, 2017 (received for
review July 27, 2017)

Significance

Focused ultrasound is currently the only method of reversible blood–brain barrier disruption for targeted drug delivery without
incision or radiation. A significant challenge for its clinical translation is a lack of reliable real-time treatment control.
Here a closed-loop, real-time control paradigm is shown capable of sustaining stable microbubble oscillations at a preset
level while minimizing microbubble behavior that may result in vascular damage. Tested at clinically relevant frequency in
healthy and tumor-bearing rats, our approach enables targeted delivery of predefined drug concentrations within a therapeutically
effective range in both normal tissue and glioma, while maintaining a safe exposure level. It can be readily implemented clinically
for delivering chemotherapeutics or other agents and potentially applied to other cavitation-enhanced ultrasound therapies.

Abstract

Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain
barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance
thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable
vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while
suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically
relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that
this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal
doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using
uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability
of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control.
It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.

Conflict of interest statement: Two provisional patents describing the controlling system and focused ultrasound system developed
in this work have been filed (inventors: N.J.M. and T.S.). N.J.M. holds another two published patents on the ultrasound technique
evaluated in this work. No conflicts of interest were disclosed by the other authors.